Cyanide is widely regarded an archetypal poison. In the United States, industrial use exceeds 1 billion pounds yearly in diverse areas including electroplating, plastics and gold extraction. Dzomback, D. A., et al., Cyanide in Water and Soil: Chemistry, Risk and Management. CRC Press: Boca Raton, Fla., 2006.
Cyanide salts are relatively easy to prepare and release hydrogen cyanide from simple reagents. The risk of mass casualties from an industrial accident is highlighted by the Bhopal disaster in 1984 and in terrorist plots to release chemical agents including cyanide in the subways of Tokyo in 1995, Chicago in 2002 and New York in 2003. Additionally, cyanide is also released during combustion of nitrogenous materials and, in addition to carbon monoxide, is a major factor in fatalities by smoke inhalation. Lecarpentier, Y., et al., N. Engl. J. Med. 1991, 325, 1761-1766; Esposito, F. M.; Alarie, Y., J. Fire Sci. 1988, 6, 195-242; and Alarie, Y., Crit. Rev. Toxicol. 2002, 32, 259-289.
The currently available cyanide antidotes in the U.S. are hydroxocobalamin (Cyanokit) and the combination of sodium nitrite and sodium thiosulfate (Nithiodote). Both these treatments are limited in that they must be administered intravenously (iv) over a period of 5-15 min. The need to establish an iv line and the slow infusion rates required render these agents unsuitable for a mass casualty setting. Development of an antidote suitable for rapid intramuscular (im) administration should address the above concerns; however, this requires an antidote that can be delivered in a small volume for rapid absorption.
There are two pathways in mammals that detoxify cyanide as thiocyanate: rhodanese (thiosulfate/cyanide sulfur transferase EC 2.8.1.2) and 3-mercaptopyruvate sulfurtransferase (3-MST, EC 2.8.1.1). While the rhodanse pathway is currently exploited clinically with sodium thiosulfate, 3-MST should be a more efficient pathway in that 3-MST is more widely distributed in tissues, including the central nervous system than rhodanese. Additionally, 3-MST is present in the cytosol as well as in mitochondria whereas rhodanese is concentrated solely in the mitochondria. The endogenous substrate for 3-MST is the deaminated cysteine catabolite, 3-mercaptopyruvate (3-MP, 1) however the poor stability of 3-MP renders this substrate a poor drug candidate. Nagahara, N., et al., Curr. Drug Targets Immune Endocr. Metabol. Disord. 2003, 3, 198-204. Thus, some efforts have focused on developing prodrugs of 3-MP. Nagasawa, H. T., et al., J. Med. Chem. 2007, 50, 6462-6464; Patterson, S. E., et al., J. Med. Chem. 2013, 56, 1346-1349; Singh, H., et al., Anesthesiology and Analgesia 2012, in press; Chan, A., et al., Clin. Toxicol. (Phila.) 2011, 49, 366-373; and Brenner, M., et al., Toxicol. Appl. Pharmacol. 2010, 248, 269-276.
                3-Mercaptopyruvic acid (1,3-MP), the endogenous substrate for 3-MST and its dithiane form (2).        
The dithiane form of 3-MP (sulfanegenic acid, 2), as a sodium salt (sulfanegen sodium, 3a) is highly effective in rescue of our sublethal murine and lethal swine models of cyanide toxicity when administered intraperitoneally (ip) and iv. Nagasawa, H. T., et al., J. Med. Chem. 2007, 50, 6462-6464; Belani, K. G., et al., Anesth. Analg. 2012, 114, 956-961; and Crankshaw, D. L., et al., Toxicol. Lett. 2007, 175, 111-117. Based on a 60 kg human with a maximum injectable volume of 5 mL dose, calculations revealed that minimal water solubility of 1.05 M was required for effective im administration. However, the aqueous solubility of sulfanegen sodium, 3a, is 0.35 M; hence 3a is not optimal for development as an im cyanide antidote.
Additionally, sulfanegen triethanolamine has been investigated for preclinical development. Patterson, S. E., et al., J. Med. Chem. 2013, 56, 1346-1349. Unfortunately, it has been determined that this sulfanegen salt has poor thermal stability with a short (<6 month) shelf life at room temperature (unpublished results). Accordingly, there is currently a need for a sulfanegen formulation that is well tolerated, has acceptable thermal stability, and is effective in lethal models of cyanide toxicity. Ideally, the formulation will be suitable for im administration.